In vitro Antileishmanial, Trypanocidal and Mammalian Cell Activities of Diverse N,N'-Dihetaryl Substituted Diamines and Related Compounds

Abstract

The leishmaniasis and Chagas diseases constitute a serious public health problem worldwide with few and ineffective treatment options. The search for new antiparasitic candidates at the initial steps of drug discovery and development is still necessary. The synthesis of 22 de novo synthetized N,N′-dihetaryl-alkyldiamine derivatives and in vitro antiparasitic activity were evaluated for the first time against intracellular and extracellular forms of Leishmania (Leishmania) infantum, L. (Viannia) panamensis, L. (Leishmania) amazonensis, and Trypanosoma cruzi. Additionally, the toxicity on mammalian cells was determined. Some of these substituted N,N′-diamines (25–35 % of the tested compounds) showed interesting results against free-living forms of parasites with activities at the inhibitory concentration (IC50) level of 1.96 to 28.83 μM for L. (L.) infantum promastigotes and IC50 of 0.02 to 5.31 μM for T. cruzi epimastigotes. No activity at the IC50 level on intracellular amastigotes of T. cruzi was observed. However, N1,N2-dibenzylethane-1,2-diamine 5a revealed an important activity against the intracellular amastigotes of L. infantum (IC50 25.42 μM ±0.33) and L. panamensis (IC50 58.20 μM ±3.23), while their analogue N1,N4-dibenzylbutane-1,4-diamine 5c resulted in activity only against L. panamensis (IC50 11.19 μM ±0.20) without toxicity on Vero and THP-1 mammalian cells. The active compounds against intracellular parasites with low toxicity in mammalian cells may be considered for future studies in experimental models.

Drug Discovery for Cutaneous Leishmaniasis: A Review of Developments in the Past 15 Years

“…Similarly, prenylated chalcones [144] and prenyloxy chalcones [145] have demonstrated both anti-leishmanial and anti-trypanosomal activity. Additional compound classes that have shown potent anti-kinetoplastid activity include binuclear cyclopalladated compounds [146], 1,3,4,5-tetrasubstituted pyrazoles [147], N,N -dihetaryl substituted diamines [148], N-benzene and N-naphthalenesulfonamide derivatives [149], thiazolyl-isatin derivatives [150], and ruthenium-purine complexes [151]. Natural products have also been an area of interest, with several researchers identifying compounds like sesquiterpene lactones [152,153] and terpenoids [154] with anti-trypanosomatid properties.…”

$$N$$ N -Polybenzylated alicyclic 1,2-diamines: cytotoxicity and G1 phase arrest in cancer cell line

“…The 1,2-diamino moiety can be found in many natural and synthetic substances showing valuable biological properties [3,4]. Among them it is possible to cite, for instance, antidepressant agents [5], antiarrhythmics [6], antimicrobial [7], antiparasitic against Leishmania spp and Trypanosoma cruzi [8,9] and anticancer drugs. Antitumoral properties of cisplatin [10] and its success in chemotherapy brought about the synthesis of many diammine-platinum complexes with improved properties, such as oxaliplatin and DWA 2114R.…”

Antiparasitic evaluation of salicylate and salicylamide derivatives

“…As yet, there are no vaccines that generate immunity in the population, and the most commonly used chemotherapy is based on pentavalent and second-generation antimonial drugs (nonantimonials) such as pentamidine isothionate (Lomidine ®), amphotericin B, paromomycin, and miltefosine. However, the high toxicity presented by these chemotherapies can cause hypoglycemia, hypotension, cardiac alterations, nephrotoxicity, and even sudden death; all of which are limiting factors for therapeutic use (LEAL et al, 2013;FIGUEREDO et al, 2022).…”